Angiotensin II (AngII) and its G protein-coupled AT1 receptor play critical roles in mediating cardiovascular diseases such as hypertension, atherosclerosis, and restenosis after vascular injury. It is widely believed that AngII promotes these diseases by inducing vascular remodeling that involves hypertrophy, proliferation, and migration of vascular smooth muscle cells (VSMCs). During our past funding period, we have shown that transactivation of an ErbB family receptor, EGF receptor (EGFR), is essential for VSMC hypertrophy and migration by AngII. Also, mature HB-EGF production/shedding through activation of a metalloprotease, ADAM17, appears to be an indispensable signaling event for the AngII-induced EGFR transactivation in VSMCs. Moreover, our past and preliminary results strongly suggest existence of Gq-derived 2nd messengers that are upstream of the ADAM17 activation via the AT1 receptor. However, the exact signal transduction mechanism(s) by which AngII promotes ADAM17 activation in VSMCs as well as its impact in mediating vascular remodeling in vivo remains unclear, and thus is essential for our research team to explore. Based on our past findings together with our recent preliminary results, we have built attractive hypotheses on the above- mentioned mechanism(s). Therefore, the specific aims of this renewal application are designed to explore the novel signal transduction concepts of the ADAM17 activation in VSMCs as well as to prove the functional and translational significance of the activation in vivo. Aim 1. To test the hypothesis that tyrosine phosphorylation and subsequent interaction with newly-identified ADAM17 binding protein(s) are essential for ADAM17 activation by the AT1 receptor in VSMCs. Aim 2. To test the hypothesis that the cholesterol-rich membrane micro-domains provide an indispensable environment for ADAM17 activation by AngII and the resultant shedding of HB-EGF. Aim 3. To test the hypothesis that activation of ADAM17 in vascular smooth muscle by the above mechanism is the critical target of intervention for prevention of vascular remodeling in vivo. Our past substantial accomplishments together with accumulating preliminary results and the significant capabilities of our research team strongly warrant the feasibilities of the entire proposal. Successful accomplishment of these specific aims will not only provide us with the critical molecular mechanisms underlying vascular remodeling stimulated by AngII, but will also contribute to the development of novel treatment strategies toward cardiovascular diseases.